期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 188, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.112024
关键词
FAK inhibitor; Thieno[3.2-d]pyrimidine; Structure-activity relationship; Apoptosis; Migration
资金
- Program for Innovative Research Team of the Ministry of Education and Program for Liaoning Innovative Research Team in University
A series of 2,7-disubstituted-thieno[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated as novel focal adhesion kinase (FAK) inhibitors. The novel 2,7-disubstituted-thieno[3,2-d]pyrimidine scaffold has been designed as a new kinase inhibitor platform that mimics the bioactive conformation of the well-known diaminopyrimidine motif. Most of the compounds potently suppressed the enzymatic activities of FAK and potently inhibited the proliferation of U-87MG, A-549 and MDA-MB-231 cancer cell lines. Among these derivatives, the optimized compound 26f potently inhibited the enzyme (IC50= 28.2 mu M) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC50 values of 0.16, 0.27, and 0.19 mu M, respectively. Compound 26f also exhibited relatively less cytotoxicity (IC50 = 3.32 mu M) toward a normal human cell line, HK2. According to the flow cytometry results, compound 26f induced the apoptosis of MDA-MB-231 cells in a dose-dependent manner and effectively arrested MDA-MB-231 cells in G0/G1 phase. Further investigations revealed that compound 26f potently suppressed the migration of MDA-MB-231 cells. Collectively, these data support the further development of compound 26f as a lead compound for FAK-targeted anticancer drug discovery. (C) 2019 Elsevier Masson SAS. All rights reserved.
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